Cardiac Fibrillation: Mechanisms and Therapy

描述(由申请人提供)： 室颤(VF)是导致心脏性猝死(SCD)的最常见原因，仅在美国每年就有30多万人死亡。然而，尽管经过了50年的分子和细胞研究，还没有出现能与植入型心脏复律除颤器相媲美的生物疗法。该计划项目的目标是通过在机制水平上更好地了解室性心动过速的发病机制，开发合理的新疗法来预防SCD。该提案继续我们的努力，从我们在心脏性猝死中的SCOR(1995-2004)开始，并在当前的计划项目(2005-2010)中继续，通过使用实验和数学生物学相结合的系统方法在分子、细胞、组织和生物体水平上整合信息来解决这一目标。沿着这些思路，本计划项目将专注于触发-底物的相互作用，中心主题涉及如何早期(EADS)和延迟(DADS)后除极，经典地被认为是心律失常的触发因素，同时增强组织底物的易损性，从而创造导致室颤和SCD的环境。我们将在这个过程中分析动态因素和先前存在的组织异质性之间的协同作用。项目1(心律失常的多尺度建模)将建立理论框架，并辅之以项目2(心律失常的细胞机制)分子/细胞水平的实验分析，项目3(心脏衰竭中的心律失常和抗心律失常靶点)的组织水平，以及项目4(心律失常治疗的分子方法)的治疗发展，由3个核心(计算机和数学核心A、生物和生物工程核心B和管理核心C)促进。总而言之，这些研究将为开发和推进针对这种主要并发症和心脏病死亡原因的新疗法提供必要的关键基础。

DESCRIPTION (provided by applicant): Ventricular fibrillation (VF) is the most common cause of sudden cardiac death (SCD), and accounts for over 300,000 deaths per year in the United States alone. However, despite 50 years of molecular and cellular research, no biological therapy has yet emerged with comparable efficacy to the implantable cardioverter- defibrillator. The objective of this proposed Program Project is to develop rational novel therapies to prevent SCD through a better understanding of the pathogenesis of VF at the mechanistic level. The proposal continues our efforts, which began with our SCOR in Sudden Cardiac Death (1995-2004) and has continued in the current Program Project (2005-2010), to address this objective by integrating information at the molecular, cellular, tissue and organism levels using a systems approach combining experimental and mathematical biology. Continuing along these lines, this Program Project will focus on trigger-substrate interactions, with the central theme related to how early (EADs) and delayed (DADs) afterdepolarizations, classically considered as arrhythmia triggers, simultaneously enhance the vulnerability of the tissue substrate to create the milieu leading to VF and SCD. We will analyze the synergism between dynamic factors and pre-existing tissue heterogeneities in this process. Project 1 (Multi-scale Modeling of Arrhythmias) will develop the theoretical framework, complemented by the experimental analysis at the molecular/cellular level in Project 2 (Cellular Mechanisms of Arrhythmias), the tissue level in Project 3 (Arrhythmias and Antiarrhythmic Targets in Failing Hearts), and therapeutic development in Project 4 (Molecular Approaches to Arrhythmia Therapy), facilitated by 3 cores (Computer and Math Core A, Biology and Bioengineering Core B, and Administrative Core C). Together, these studies will provide critical groundwork necessary to develop and advance novel therapies for this major complication and cause of mortality from heart disease.